Abstract 4984: Integrated platform enables KRAS-targeted drugs discovery

Abstract

Abstract The Kirsten rat sarcoma viral oncogene homolog (KRAS) is mutated in approximately 25% of all human cancers and is known to be a major player promoting and maintaining tumorigenesis through the RAS-MAPK pathway. Activating mutations in KRAS increase the ability for GTP-loading, making it difficult to displace, thus constitutively activate downstream MAPK pathway and promote cancer formation. Fortunately, a revolutionary strategy to use covalent allosteric inhibitors that target a shallow pocket on the KRAS surface has provided new impetus for KRAS inhibitor development efforts. These inhibitors, such as AMG510 and MRTX849, show promising results in patients with tumors harboring KRAS G12C mutation. While the approval of AMG510 was a major breakthrough for those patients harboring KRAS G12C mutations, G12C only accounts for a fraction of those with KRAS mutations and eventual resistance to G12C inhibitors is unavoidable. Therefore, develop new drugs direct various KRAS mutants and combination strategies that target resistance mechanisms have become vital in the war against KRAS-mutant tumors. To enable the discovery of novel KRAS inhibitors, we established a one-stop service platform, covering affinity detection of compounds to KRAS mutants, KRAS upstream and downstream protein-protein interaction detection, pathway activation detection, cell proliferation assay (2D/3D culture system), and in vivo efficacy evaluation in KRAS mutant xenograft models. Our platform provides assays on nearly all the current mainstream mutants of KRAS, such as G12C/G12D/G12R/G12S/G13D, and engineered Ba/F3 cell lines that harboring single or double KRAS mutation. In addition, we developed a panel of resistant models to KRAS G12C inhibitor that bringing a better understanding of the biological basis of drug resistance, and will serve as a new tool to optimize KRAS-G12C inhibitor regimens and combinatorial strategies. The comprehensive KRAS-targeted drug discovery platform is empowering new drug research and development. Citation Format: Beibei Liu, an Li, Xiangyang Zuo, Jie Yang, Ruifeng Wang, Feifei Fan, Wenting Shi, Qingyang Gu. Integrated platform enables KRAS-targeted drugs discovery. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 4984.